Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Combination regimens against human immunodeficiency virus type 1 (HIV-1) were studied in granulocyte-macrophage colony-stimulating factor (GM-CSF)-stimulated monocyte/macrophage cultures. Regimens included those that inhibited the same target (reverse transcriptase) or multiple targets. Treatment conditions assessed efficacy during prophylaxis and ongoing infection. Drugs included zidovudine, didanosine, nevirapine, foscarnet, pyridinone, the protease inhibitor RO31-8959 (also known as saquinavir), interferon-alpha A, the Tat inhibitor RO24-7429, and N-butyl-deoxynojirimycin. Two-, three-, and four-drug combinations were tested. Drugs were tested at individually inhibitory concentrations of IC99, IC95, IC75, and IC50. All prophylactic regimens prevented HIV-1 replication at IC99. As drug concentrations were reduced, differences among the regimens became apparent. Regimens that acted at both single and multiple targets were effective in prophylactic settings and less so in acute infection. In ongoing infections, only modest reductions in viral replication were seen, even at IC99.
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PMID:Inhibition of human immunodeficiency virus type 1 replication in cytokine-stimulated monocytes/macrophages by combination therapy. 752 25

Delavirdine (bisheteroarylpiperazine, U-90152), a nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1), was evaluated in a two-drug combination with recombinant human interferon-alpha (IFN-alpha) or the peptidomimetic protease inhibitor U-75875 against HIV-1 replication in vitro. Viral growth was assayed in a CD4+ T cell line (H9) infected with HIVIIIB and in human peripheral blood mononuclear cells infected with the clinical isolate HIVJRCSF. Drug synergy, estimated by the combination index method and the method of Pritchard and Shipman, was observed when delavirdine was combined with U-75875 or IFN-alpha over a range of drug concentrations (delavirdine: 0.001, 0.003, 0.01, 0.03 microM; U-75875: 0.01, 0.03, 0.1, 0.3, 1.0 microM; IFN-alpha: 2, 6, 17, and 50 or 10, 30, 100, and 300 IU/mL). The combinations showed no detectable drug antagonism or cytotoxicity. These in vitro synergy data support the potential use of delavirdine with either a protease inhibitor or IFN-alpha in patients with AIDS.
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PMID:In vitro inhibition of human immunodeficiency virus type 1 by a combination of delavirdine (U-90152) with protease inhibitor U-75875 or interferon-alpha. 752 53

In contrast to therapeutic benefits of interferon-alpha (IFN-alpha) in patients with human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), little is known about the mechanisms underlying its clinical efficacy. To investigate the anti-viral and/or immunomodulatory properties of IFN-alpha in HTLV-I infection, the effects of IFN-alpha on HTLV-I-induced in vitro phenomena were evaluated. In vitro activation of HTLV-I in fractionated CD4+ T lymphocyte-rich cells (CD4+ cells) could be demonstrated by increased thymidine incorporation into the cells, detection of proviral HTLV-I and viral RNA, and by assays of reverse transcriptase activities in culture supernatants. T cell immune responses were evaluated by thymidine incorporation into CD8+ T lymphocyte-rich cells (CD8+ cells) responding to cultured and irradiated autologous CD4+ cells possessing HTLV-I antigens. It could be shown that IFN-alpha suppressed both the in vitro activation of HTLV-I and the CD8+ cell response. Moreover, 1 day supplementation of IFN-alpha as a pretreatment was sufficient for the induction of these properties. These findings, together with the clinical efficacy of IFN-alpha administration in patients with HAM/TSP, support the view that viral activation and T cell responses are critical components in the pathogenic processes involved in HAM/TSP.
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PMID:Anti-viral and immunomodulatory effects of interferon-alpha on cultured lymphocytes from patients with human T lymphotropic virus type I-associated myelopathy (HAM/TSP). 759 57

Various cobalamins act as important enzyme cofactors and modulate cellular function. We investigated cobalamins for their abilities to modify productive human immunodeficiency virus-1 (HIV-1) infection of hematopoietic cells in vitro. We show that hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl), and adenosylcobalamin Ado-Cbl (Ado-Cbl) inhibit HIV-1 infection of normal human blood monocytes and lymphocytes. The inhibitory effects were noted when analyzing the monocytotropic strains HIV-1-BaL and HIV-1-ADA as well as the lymphocytotropic strain HIV-1-LAI. Cobalamins did not modify binding of gp120 to CD4 or block early steps in viral life cycle, inhibit reverse transcriptase, inhibit induction of HIV-1 expression from cells with established or latent infection, or modify monocyte interferon-alpha production. Because of the ability to achieve high blood and tissue levels of cobalamins in vivo and the general lack of toxicity, cobalamins should be considered as potentially useful agents for the treatment of HIV-1 infection.
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PMID:Inhibition of productive human immunodeficiency virus-1 infection by cobalamins. 763 33

The constitutive production of interferon-alpha (IFN-alpha) subtypes by the lymphoblastoid cell lines, Namalwa, Daudi and Raji, was investigated using sensitive and semi-quantitative flow cytometric techniques. Further, we sought to determine whether the previously described failure of these cell lines to produce IFN-alpha-4 was a result of the deletion of the IFN A4 gene. Cytoplasmic production of IFN-alpha-2 and IFN-alpha-4 was assessed using IFN-alpha subtype-specific antipeptide antibodies and FITC-labelled secondary antibodies in indirect immunofluorescence-flow cytometry studies. The constitutive production of IFN-alpha-2 was detected in all three cell lines. Significant increases in fluorescence representing increased production of IFN-alpha-2 and possibly other IFN-alpha subtypes were detected after induction by Sendai virus. Approximately 100 per cent of cells in the Namalwa, Daudi and Raji cell populations contained IFN-alpha-2 before and after induction. However, no cells from the same cell populations contained the IFN-alpha-4 subtype. Analysis of genomic DNA isolated from the lymphoblastoid cells using the Polymerase Chain Reaction (PCR) and oligonucleotide primers specific for IFN A2 or IFN A4 confirmed the presence of the genes encoding both IFN-alpha subtypes. Furthermore, using reverse transcriptase-PCR amplification, mRNAs for both IFN-alpha-2 and IFN-alpha-4 were detected. Therefore, in contrast to some leukaemias and derived cell lines where IFN A genes have been deleted, these cell lines of B cell lineage exhibit selective expression of IFN A genes, as a result of altered transcriptional/translational control of IFN-alpha expression.
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PMID:Post-transcriptional regulation of interferon-alpha 4 subtype production by lymphoblastoid cells. 768 81

Forty-five subjects with symptomatic human immunodeficiency virus type 1 (HIV-1) infection, CD4+ lymphocyte counts of > or = 150 x 10(6)/L, and Karnofsky scores > or = 60 were enrolled in a multicenter, randomized, controlled trial that compared zidovudine monotherapy and combination therapy for 48 weeks with zidovudine and interferon-alpha (IFN-alpha). Zidovudine with IFN-alpha (n = 25) had a favorable effect on CD4+ cell counts compared with zidovudine alone (n = 20). At all time points analyzed, the mean change from baseline was higher, reaching significance at week 24 (+10% versus -21%; P = .029). At week 48 the difference was -12% versus -45% (P = .07). Anti-CD3 monoclonal antibody-induced T cell reactivity improved temporarily in both groups. Serum HIV p24 antigen levels decreased maximally during the first 12 weeks of treatment. At weeks 0 and 48, polymerase chain reaction analysis for mutations at codons 67 and 215 of the HIV-1 reverse transcriptase gene conferring zidovudine resistance was conducted in 10 subjects receiving zidovudine and in 8 subjects receiving combination therapy. At week 48, 1 of 8 and 4 of 6 samples from the groups receiving zidovudine only or combination therapy, respectively, contained wild type virus at codon 215. Grade 3 or 4 toxicity was uncommon. Drug-related malaise and anorexia were observed more frequently in patients receiving both zidovudine and IFN-alpha.
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PMID:Zidovudine and interferon-alpha combination therapy versus zidovudine monotherapy in subjects with symptomatic human immunodeficiency virus type 1 infection. 791 Aug 38

Interferon-alpha induces durable cytogenetic remissions in about one-quarter of newly diagnosed patients with chronic myelogenous leukemia (CML). Even so, after short-term follow-up, previous studies have shown that residual leukemic cells can be detected by the polymerase chain reaction (PCR) in all of these individuals. The objectives of our study were therefore to obtain long-term follow-up data on residual disease in a cohort of complete responders and to determine if leukemic cells with clonogenic potential are present in patients despite the absence of relapse. We performed (a) serial analysis of blood and/or bone marrow for a reverse transcriptase PCR amplified BCR-ABL transcript at times well beyond the point that cytogenetic remission was first attained and (b) reverse transcriptase PCR of individually plucked myeloid and erythroid colonies for the presence of the same transcript. Seven CML patients who had previously attained complete cytogenetic remission while on interferon-alpha were investigated. Six of the seven patients were in complete cytogenetic remission at the time of analysis, whereas one patient had early evidence of cytogenetic relapse. With ongoing therapy, five patients with the longest follow-up eventually achieved PCR negativity at time periods of 27, 32, 36, 49, and 67 mo after a complete cytogenetic remission was first noted. Even so, residual disease was detected in progenitor cells derived from two patients, each of whom had been in continuous cytogenetic remission for approximately 2.5 and 3.5 yr, respectively. Progenitors expressing BCR-ABL transcripts were also detected in the patient with early cytogenetic relapse. These observations demonstrate that residual disease resides in colony-forming cells that should have the potential to repopulate the bone marrow. However, the presence of a minority of Ph-positive CML progenitor cells for a very long period of time is still compatible with durable remission, confirming that a situation of tumor dormancy may be induced in CML by interferon therapy.
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PMID:Persistence of dormant leukemic progenitors during interferon-induced remission in chronic myelogenous leukemia. Analysis by polymerase chain reaction of individual colonies. 792 13

The expression of three chemoattractant cytokine (chemokine) messenger (m)RNAs in the murine renal cell carcinoma (RENCA) from mice treated with a combination of interferon-alpha (IFN-alpha) and interleukin-2 was examined and related to tumor infiltration by inflammatory leukocytes. Using a semi-quantitative reverse transcriptase polymerase chain reaction assay, mRNAs encoding the KC, JE, and IP-10 genes were all elevated in tumor tissue from mice treated systemically with IFN-alpha/interleukin-2 for 4 days. Similarly, the mRNA for tumor necrosis factor-alpha (TNF-alpha) was also increased in tumors from treated as compared to control animals. The same tumors showed a significant increase in Mac-1+ leukocytes, which correlated well with the increase in chemokine and TNF-alpha gene expression. The renal cell carcinoma tumor itself may be responsible for the expression of chemokine genes in the tumor bed following cytokine therapy. Cultures of freshly explanted RENCA cells expressed significant levels of chemokine mRNAs when stimulated in vitro with IFN alpha, IFN gamma, and/or interleukin-2, demonstrating that this tumor cell has potential for expression of these genes in vivo. In contrast, TNF-alpha expression was not detected in cultured tumor cells. Thus TNF-alpha may be expressed by infiltrating monocytes following exposure to recombinant cytokine therapy.
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PMID:Chemokine gene expression in the murine renal cell carcinoma, RENCA, following treatment in vivo with interferon-alpha and interleukin-2. 816 Jul 74

Previous studies in patients receiving interferon-alpha (IFN-alpha) therapy and patients with systemic lupus erythematosus have demonstrated that elevated cerebrospinal fluid (CSF) levels of IFN-alpha are associated with cognitive dysfunction. We measured IFN-alpha levels in CSF and blood by ELISA in human immunodeficiency virus (HIV)-positive patients with (n = 21) and without (n = 23) dementia and HIV-negative controls (n = 48). IFN-alpha was significantly elevated in the CSF of HIV-positive patients with dementia compared to those without dementia and controls. An increasing amount of IFN-alpha in the CSF was correlated with the clinical parameter of increasing Memorial Sloan Kettering scores; although these correlations were not statistically significant, they further suggest an association of increased CSF IFN-alpha with neurocognitive dysfunction in AIDS. Immunocytochemical staining of brains demonstrated IFN-alpha-positive macrophages and astrocytes in frontal cortex and white matter and IFN-alpha mRNA was detected by reverse transcriptase-polymerase chain reaction, further indicating that IFN-alpha is made by cells within the brain and suggesting that the significant increases of IFN-alpha protein found in the CSF of patients with HIV-associated dementia complex are derived from intrinsic brain cells such as macrophages and astrocytes. Increased local production of IFN-alpha during HIV infection may contribute directly or indirectly to the pathogenesis of HIV-associated dementia.
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PMID:A potential role for interferon-alpha in the pathogenesis of HIV-associated dementia. 890 53

Several anti-HIV drugs acting on different steps of virus replication were tested in our experimental model of primary monocyte/macrophages; the results were compared with the activity found in lymphocytes. Nucleoside analogues (AZT, ddI, ddC, d4T, PMEA, 3TC etc.) show greater activity in macrophages (M/M) than in lymphocytes. In particular, the EC50 of AZT, ddC, and ddI in M/M is 2- to 100-fold lower than that found in lymphocytes. This greater efficacy of nucleoside analogues in M/M depends on the enhancement of their chain-terminating activity by the low levels of endogenous deoxynucleoside-triphosphates (dNTP) usually found in resting cells such as M/M. Non-nucleoside reverse transcriptase inhibitors (NNRTI) do not act as chain terminators (thus their antiviral effect is not related to the intracellular concentrations of dNTP); as a consequence the activity of TSAO, HEPT, TIBO, and other NNRTI tested in M/M is similar to that found in lymphocytes. Regarding inhibitors of binding and fusion of HIV, we found that their anti-HIV activity is markedly decreased (or even nullified) when M/M are treated with cytokine activators of M/M function and enhancers of HIV replication. More relevant from a clinical standpoint, protease inhibitors are able to inhibit HIV replication in chronically infected macrophages (i.e., cells carrying the proviral genome already integrated in the host genome). All other inhibitors of late stage of virus life cycle tested (antisense-rev, anti-tat, interferon-alpha and -gamma, phosphorothioate analogues, GLQ-223, etc.) were totally inactive in chronically infected macrophages. The different effects of various classes of HIV inhibitors in lymphocytes and macrophages suggests that AIDS therapy should consider all aspects of the pathogenesis of HIV infection and must be restricted to drugs, or combinations of drugs, active against both lymphocytes and M/M in all body compartments where the virus hides and replicates.
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PMID:Inhibition of replication of HIV in primary monocyte/macrophages by different antiviral drugs and comparative efficacy in lymphocytes. 922 5


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